COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinfla...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2020.599502/full |
| _version_ | 1828964601143754752 |
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| author | Cirino Botta Alessia Indrieri Alessia Indrieri Eugenio Garofalo Flavia Biamonte Andrea Bruni Pino Pasqua Francesco Cesario Francesco Saverio Costanzo Federico Longhini Francesco Mendicino |
| author_facet | Cirino Botta Alessia Indrieri Alessia Indrieri Eugenio Garofalo Flavia Biamonte Andrea Bruni Pino Pasqua Francesco Cesario Francesco Saverio Costanzo Federico Longhini Francesco Mendicino |
| author_sort | Cirino Botta |
| collection | DOAJ |
| description | Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy. |
| first_indexed | 2024-12-14T10:52:37Z |
| format | Article |
| id | doaj.art-692a35dc02544dd49f0a069f3b81116c |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T10:52:37Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-692a35dc02544dd49f0a069f3b81116c2022-12-21T23:05:07ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-01-011010.3389/fonc.2020.599502599502COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine StormCirino Botta0Alessia Indrieri1Alessia Indrieri2Eugenio Garofalo3Flavia Biamonte4Andrea Bruni5Pino Pasqua6Francesco Cesario7Francesco Saverio Costanzo8Federico Longhini9Francesco Mendicino10Hematology Unit, Department of Hemato-Oncology, “Annunziata” Hospital of Cosenza, Cosenza, Italy Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, ItalyInstitute for Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, ItalyAnesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University, Catanzaro, ItalyDepartment of Clinical and Experimental Medicine, “Magna Graecia” University, Catanzaro, ItalyAnesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University, Catanzaro, ItalyAnesthesia and Intensive Care Unit, “Annunziata” Hospital of Cosenza, Cosenza, ItalyHematology Unit, Department of Hemato-Oncology, “Annunziata” Hospital of Cosenza, Cosenza, ItalyDepartment of Clinical and Experimental Medicine, “Magna Graecia” University, Catanzaro, ItalyAnesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, “Magna Graecia” University, Catanzaro, ItalyHematology Unit, Department of Hemato-Oncology, “Annunziata” Hospital of Cosenza, Cosenza, ItalySince SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available therapeutic-strategies to overcome CRS, should be urgently evaluated for their capability of reducing COVID-19 mortality. Notably, COVID-19 shares different pathogenic aspects with acute graft-versus-host-disease (aGVHD), hemophagocytic-lymphohistiocytosis (HLH), myelofibrosis, and CAR-T-associated CRS. Specifically, similarly to aGVHD, an induced tissue damage (caused by the virus) leads to increased cytokine release (TNFα and IL-6) which in turn leads to exaggerated dendritic cells, macrophages (like in HLH) and lymphocytes (as in CAR-T) activation, immune-cells migration, and tissue-damage (including late-stage fibrosis, similar to myelofibrosis). Janus Kinase (JAK) signaling represents a molecular hub linking all these events, rendering JAK-inhibitors suitable to limit deleterious effects of an overwhelming inflammatory-response. Accordingly, ruxolitinib is the only selective JAK1 and JAK2-inhibitor approved for the treatment of myelofibrosis and aGVHD. Here, we discuss, from a molecular and hematological point of view, the rationale for targeting JAK signaling in the management of COVID-19 patients and report the clinical results of a patient admitted to ICU among the firsts to be treated with ruxolitinib in Italy.https://www.frontiersin.org/articles/10.3389/fonc.2020.599502/fullCOVID-19ruxolitinibhyperinflammationferritinJAK2 |
| spellingShingle | Cirino Botta Alessia Indrieri Alessia Indrieri Eugenio Garofalo Flavia Biamonte Andrea Bruni Pino Pasqua Francesco Cesario Francesco Saverio Costanzo Federico Longhini Francesco Mendicino COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm Frontiers in Oncology COVID-19 ruxolitinib hyperinflammation ferritin JAK2 |
| title | COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm |
| title_full | COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm |
| title_fullStr | COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm |
| title_full_unstemmed | COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm |
| title_short | COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm |
| title_sort | covid 19 high jaking of the inflammatory flight by ruxolitinib to avoid the cytokine storm |
| topic | COVID-19 ruxolitinib hyperinflammation ferritin JAK2 |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2020.599502/full |
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